BHIVA) Guidelines for the Treatment of HIV-Infected Adults with Antiretroviral Therapy (2006

r 2006 British HIV Association HIV Medicine (2006), 7, 487–503 British HIV Association (BHIVA) guidelines for the treatment of HIV-infected adults with antiretroviral therapy (2006) B Gazzard on behalf of the BHIVA Writing Committee* Introduction attributed to staffing but this also included $72 per annum for patient incentives, which are unlikely to be deployed in This summary document is an update to the full British HIV the UK. Although it is difficult to extrapolate these costs to Association (BHIVA) Treatment Guidelines published in NHS services in the UK, the absolute cost of adherence HIV Medicine in July 2005 (Volume 6, Supplement 2). Only interventions appears to be relatively low, and slightly less the ‘What to start with’ and ‘Treatment-experienced than that of a genotype resistance test [5]. patients’ sections have been completely rewritten. The tables of recommendations (Tables 1–7) have also been updated to include new data. Please refer to the full When to start treatment guidelines for more information. Primary HIV infection Adherence No new data have emerged in the past year to change the view of the Committee that, if antiretroviral therapy is Since the last version of these guidelines there have been started in the context of primary HIV infection, it should few new data relating to adherence to medication in normally only be in the setting of a clinical trial (e.g. the general, or to highly active antiretroviral therapy (HAART) MRC SPARTAC study [6]). in particular. Studies continue to support a role for brief interventions including treatment-related education and individualized adherence problem-solving in increasing Established HIV infection adherence (at least over the following months) [1,2]. A Decisions on when to start treatment are based on an study looking at using long-term partners to support assessment of the risk of disease progression over the adherence showed a marked beneficial effect on adherence medium term if treatment is not started (e.g. using data in the short term, but this was not sustained at 6 months from the CASCADE collaboration [7]), vs. the potential [3]. In the Gilead 934 study, although adherence (measured risks of starting treatment earlier (toxicity and resistance). by pill count) was statistically significantly higher in the The risk of disease progression is determined largely by the once-daily arm vs. twice-daily, the clinical difference was CD4 cell count, plasma viral load and the age of the patient. small (3%) and may have arisen because of the poorer No new data have emerged since the previous guidelines to tolerability of the twice-daily arm rather than because of alter the Committee’s view that treatment should start any benefit of once-daily dosing [4]. before the CD4 cell count has fallen to below 200 cells/mL. Research in the USA examined the costs in real terms of This is because of the higher risk of death or disease delivering a variety of adherence interventions over the progression in patients who delay starting treatment until first year of patient support. The majority of interventions their CD4 cell count has fallen to this level, and the reduced were delivered by nurses. Median direct annual cost was efficacy of HAART when introduced at a count of $420 (range $60–700) per patient; 66% of this was o200 cells/mL in some studies. The implication of this is that earlier diagnosis of infection remains paramount; this Correspondence: Professor Brian Gazzard, Chelsea and Westminster is only likely to be achieved by much more widespread and Hospital, 369 Fulham Road, London, SW10 9NH, UK. normalized use of HIV antibody testing [8]. In patients with e-mail: [email protected] counts above this level, the risk of disease progression *BHIVA Writing Committee members and contributors: EJ Bernard, M Boffito, D Churchill, S Edwards, M Fisher, AM Geretti, M Johnson, C Leen, without therapy should be considered. Therapy should be B Peters, A Pozniak, J Ross, J Walsh, E Wilkins and M Youle started if the patient wishes to start, the medium-term risk 487 488 B Gazzard of disease progression is high (e.g.42–4% in 6 months) What to start with and the likelihood of harm as a result of drug toxicity or There is overwhelming evidence from cohort studies that the selection of resistant virus is considered to be low. This the very dramatic fall in AIDS-related mortality and is likely to mean that the majority of patients with CD4 frequency of AIDS events seen in the developed world counts 4350 cells/mL should continue to defer treatment. over the last 10 years coincides with the introduction of Although cohort studies [9–11] have consistently shown that HAART. Further improvements in treatment have led to the risk of disease progression in this group tends to be lower fewer naı¨ve patients now failing first-line therapy. foruptoseveralyearsiftherapyis started earlier, this is at the Measurement of the success of a regimen is achieving a cost of significant drug toxicity, necessitating drug switching viral load of o50 HIV-1 RNA copies/mL within 3–6 or stopping therapy in a significant minority [9], and the months of starting therapy and then maintaining this absolute risk of disease progression in this group remains thereafter. Regardless of the baseline viral load, a level of very low. Other cohort studies (albeit in patient groups using 1000 copies/mL has been found to be achievable in the regimens that might not be recommended currently [12,13]) majority of people by 4 weeks from start of therapy. Failure have demonstrated that selection of drug-resistant virus to achieve this is strongly associated with failure to reach occurs in 25% of patients after 2–3 years, suggesting that viral load below 50 copies/mL within 24 weeks. A viral load deferral of initiation may preserve future treatment options. above 1000 copies/mL measured 4 weeks after the initiation Patients randomized to the drug conservation (DC) arm of therapy therefore should prompt questions over possible (i.e. intermittent therapy) of the SMART study [14] had a poor adherence or other reasons such as reduced drug significantly increased risk of opportunistic infection or levels or primary drug resistance. death after 16 months of follow up compared to those in HAART regimens should be individualized in order to the virological suppression (VS) arm (i.e. continuous achieve the best potency, adherence and tolerability; to therapy). Importantly, this benefit was seen across all minimize potential long-term toxicity and to avoid any CD4 cell count strata, not only in those with a nadir CD4 likely drug–drug interactions. The cost of the regimen should count of o350 cells/mL. These data have been interpreted also be considered. as evidence that drug treatment should be started at an earlier stage than is currently the case. However, analyses of the relative rates of disease progression in the two arms Which HAART regimen is best? indicate that the absolute risk of disease progression remains relatively low in the DC arm of the study Previous guidelines have been hampered by the paucity of (approximately 2% per year compared to 1% in the VS published data to definitively inform whether HAART arm). This is consistent with existing data from cohort based around a non-nucleoside reverse transcriptase studies, and as such does not provide convincing evidence inhibitor (NNRTI) or boosted protease inhibitor (PI) regimen to change the recommendations of the 2005 guidelines. is preferable. Moreover, there have been only limited data Rather, this reinforces the evidence that there is a on comparative efficacy among boosted PIs. continuous increase in the risk of disease progression and Studies have shown the superiority of efavirenz (EFV)- death in untreated patients as the CD4 cell count falls, and containing regimens over nelfinavir (NFV)-, boosted saqui- that decisions on starting therapy need to be individua- navir (SQV)- and boosted amprenavir-containing regimens lized, taking into account the specific circumstances and [16–18]. A recently presented controlled trial comparing a risks present in each patient. Patients in the DC arm were currently recommended boosted PI [ritonavir-boosted lopi- also found to have much higher rates of cardiovascular, navir (LPV/r)] with EFV in naı¨ve patients has demonstrated renal and hepatic disease than were seen in the VS arm. If on intention-to-treat (ITT) analysis the superiority of an this phenomenon is attributable to the effect of untreated EFV-based HAART regimen over 96 weeks [19]. This HIV infection, this would be a further argument for earlier resulted from a lower rate of virological failure in the EFV therapy. As the tolerability and toxicity profiles of initial arm, with no significant difference between the arms in therapy improve and the risk of selecting resistant virus treatment-limiting toxicity. Less class-emergent resistance with initial therapy falls [15], it will increasingly become and improved immunological response was, however, seen reasonable to consider starting therapy earlier than in the boosted LPV arm. In addition, a 48-week study previously (i.e. earlier in the CD4 count range 200– comparing LPV/r with ritonavir-boosted fosamprenavir 350 cells/mL, and above counts of 350 cells/mL in selected (FOS/r) has demonstrated the noninferiority of twice-daily patients, such as older patients, those with higher viral FOS/r at all CD4 cell count and viral load strata [20]. load, and those with other comorbidities such as hepatitis B It is important to select the regimen best suited to the or C virus infection). individual patient, and therefore to fully assess baseline r 2006 British HIV Association HIV Medicine (2006) 7, 487–503 BHIVA guidelines 489 risk factors for resistance, hepatitis B/hepatitis C virus in some countries/groups, increasing incidence of primary coinfection, cardiovascular disease, diabetes, and psychia- resistance.

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